Cetirizine, chemically 2-[4-[(4-chlorophenyl)-phenyl-methyl]piperazin-1-yl]ethoxy]acetic acid, is a useful pharmaceutical active ingredient. It is an antihistamine whose principal effects are mediated via selective inhibition of H1 receptors. This anti-allergy drug is marketed by the company UCB (which is also the originator of the drug) and/or Pfizer under the brand name Zyrtec®, as a dihydrochloride salt (often referred to as “cetirizine hydrochloride”) as shown below.

The drug is indicated for the relief of symptoms associated with seasonal allergic rhinitis or perennial allergic rhinitis, as well as for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.
Cetirizine has one asymmetric carbon, therefore it may be resolved into enantiomers. The pharmaceutically active enantiomer in the racemic cetirizine is the levocetirizine, which is the (R) enantiomer of cetirizine. A medicament comprising levocetirizine was launched in the first quarter of 2001 in Germany followed by a pan-European launch. Levocetirizine is also marketed as the dihydrochloride salt, under the brand name Xyzaal®.
Cetirizine was disclosed in U.S. Pat. No. 4,525,358 (EP 58146). Levocetirizine was specifically disclosed in GB2225321. The method of use of levocetirizine has been disclosed in U.S. Pat. No. 5,698,558 (EP 663828).
Conventionally, levocetirizine may be obtained by resolution of the cetirizine enantiomers as generally suggested, e.g., in WO 94/06429. However, the effectiveness of such process is apparently not high and therefore it is preferred to make levocetirizine from an enantiopure intermediate.
One such useful intermediate is the compound of formula (4)

The presence of a quarternary carbon in the formula (4) indicates that the compound may be obtained as a racemate or as a single enantiomer, particularly as the (R) enantiomer. This intermediate may be converted to cetirizine or related analogues, particularly to racemic cetirizine or levocetirizine, by various known processes, e.g., by processes reviewed in U.S. Pat. No. 4,525,358. Resolution of the intermediate (4) into enantiomers by L-tartaric acid as well as the process for making levocetirizine from the corresponding enantiomer of (4) was disclosed in GB2225321. However, the yield and effectiveness of the resolution is insufficient, as shown in U.S. Pat. No. 5,478,941.
The useful starting material for making the compound (4) is the well known and commercially available compound of formula (1),

Similarly as the above compound (4), the compound (1) may be obtained as a racemate or as a single enantiomer, particularly as the (R) enantiomer. It is known that the racemic compound (1) can be easily and effectively resolved into enantiomers by a fractional crystallization, preferably by the crystallization of salts with L-tartaric acid. (see U.S. Pat. No. 5,478,941). This makes the compound (1) an important intermediate, particularly in the synthesis of an enantiomerically pure (4).
In a known process for making compound (4) disclosed in EP 617028 (U.S. Pat. No. 5,478,941), the racemic compound of formula (1) and/or its (R)-enantiomer is subjected to a condensation with the N-sulfonated bis-chloroethylamine compound of formula (2),

to form the compound of formula (3).

The compound (3) is then deprotected to form the key intermediate of general formula (4). A disadvantage, however, with the use of the compound of formula (2) in the synthesis of the compound of formula (4) is the need to use a strong deprotecting agent. The tosyl-protective group may be effectively removed only by using a solution of hydrogen bromide in acetic acid. This agent is extremely corrosive, irritating and toxic so that special measures must be used in employing this material.
In principle, one could expect that also an unprotected compound of the formula (5a)
might be used for coupling with the compound (1). This would avoid the deprotection step and form the compound (4) directly. But this option is not satisfactory. First, the compound (5a) is an extremely toxic compound (“mustard gas”), and second the reaction is accompanied with a large amount of side products arising particularly from the self-condensation of the compound (5). Thus, the use of an N-protected bis-haloethylamine is clearly preferable. But other potentially useful N-protected compounds, e.g. a carbonyl, alkyl or a triphenylmethyl protecting group, have been reported as unsatisfactory. U.S. Pat. No. 5,478,941 and EP 955295 teach that the above mentioned N-tosyl compound of formula (2) is the only useful compound for the coupling reaction with (1). The protected analogues (a carbonyl, alkyl, or trityl protecting group) caused important racemization of the compound (1) during the coupling reaction and/or the formation of undesired by-products.
Opalka C. J. et al. (Synthesis 1995 (7), p. 766-768) reports that the coupling reaction failed if the amides of formula 6, wherein R represents a carbon-terminated substituent, were used.

Thus other protecting groups have proven to be unsuitable so far. It would be desirable to have an alternative process for making the compound of general formula (A), particularly for making the racemate or the R-enantiomer thereof.